MED15, encoding a subunit of the mediator complex, is overexpressed at high frequency in castration-resistant prostate cancer

作者：Shaikhibrahim Zaki; Menon Roopika; Braun Martin; Offermann Anne; Queisser Angela; Boehm Diana; Vogel Wenzel; Rueenauver Kerstin; Ruiz Christian; Zellweger Tobias; Svensson Maria; Andren Ove; Kristiansen Glen; Wernert Nicolas; Bubendorf Lukas; Kirfel Jutta; Biskup Saskia; Perner Sven^*

来源：International Journal of Cancer, 2014, 135(1): 19-26.

DOI：10.1002/ijc.28647

• castration-resistant
• prostate cancer
• MED15
• TGF-beta

The mediator complex is an evolutionary conserved key regulator of transcription of protein-coding genes and an integrative hub for diverse signaling pathways. In this study, we investigated whether the mediator subunit MED15 is implicated in castration-resistant prostate cancer (CRPC). MED15 expression and copy number/rearrangement status were assessed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH), respectively on 718 prostate cancer (PCa) specimens and sequenced by Sanger on a subset. Furthermore, SMAD3 phosphorylation, androgen receptor (AR) and proliferation markers were evaluated by IHC. In PCa cells, siRNA/shRNA knockdown of MED15 was followed by proliferation assays with/without dihydrotestosterone (DHT), and treatments with recombinant TGF-beta 3. Our results show that MED15 is overexpressed in 76% of distant metastatic CRPC (CRPCMET) and 70% of local-recurrent CRPC (CRPCLOC), in contrast to low frequencies in androgen-sensitive PCa, and no expression in benign prostatic tissue. Furthermore, MED15 overexpression correlates with worse clinical outcome thus defining a highly lethal phenotype. Moreover, TGF-beta signaling activation associates with MED15 overexpression in PCa tissues, and leads to increased expression of MED15 in PCa cells. MED15 knockdown effects phosphorylation and shuttling of p-SMAD3 to the nucleus as well as TGF-beta-enhanced proliferation. In PCa tissues, MED15 overexpression associates with AR overexpression/amplification and correlates with high proliferative activity. MED15 knockdown decreases both androgen-dependent and -independent proliferation in PCa cells. Taken together, these findings implicate MED15 in CRPC, and as MED15 is evolutionary conserved, it is likely to emerge as a lethal phenotype in other therapeutic-resistant diseases, and not restricted to our disease model.

• 出版日期2014-7-1